Prostaglandins for management of retained placenta

1 Department of Obstetrics & Gynecology and Clinical Research Institute, Faculty of Medicine, National University of Colombia,Bogota, Colombia. 2 Department of Statistics, School of Sciences, National University of Colombia, Bogot, D.C., Colombia

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT

Background

Retained placenta affects 0.5% to 3% of women following delivery and it is a major cause of maternal death due to postpartumhaemorrhage. Usually, retained placenta has been managed by manual removal or curettage under anaesthesia, which may be associatedwith haemorrhage, infection and uterine perforation. Medical management to facilitate the delivery of the retained placenta could bea safe alternative avoiding surgical intervention.

Objectives

To assess the effectiveness and safety of prostaglandins for the management of retained placenta.

Search methods

We searched the Cochrane Pregnancy and Childbirth Groups Trials Register (1 December 2013), LILACS (1982 to 1 December 2013),SciELO (1998 to 1 December 2013), Web of Science (2001 to 1 December 2013), openSIGLE (1997 to 1 December 2013), WorldHealth Organization International Clinical Trials Registry Platform (ICTRP) (1 December 2013) and the metaRegister of ControlledTrials (mRCT) (1 December 2013). We also contacted authors of included studies and reviewed the reference lists of retrieved studies.

Selection criteria

Randomised controlled clinical trials comparing the use of prostaglandins (or prostaglandin analogues) with placebo, expectant man-agement, tocolytic drugs, any other prostaglandins or surgical interventions for the management of retained placenta after vaginaldelivery of singleton live infants of 20 or more weeks of gestation.

Data collection and analysis

Two review authors independently assessed trials for inclusion and assessed trial quality. Two review authors independently extracteddata. Data were checked for accuracy. Any disagreements were resolved through consensus or consultation with a third review authorwhen required. Authors of the included studies were contacted for additional information.Prostaglandins for management of retained placenta (Review) 1Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.Main resultsWe included three trials, involving 244 women. The studies were considered to be at high risk of bias.The prostaglandins used were PG E2 analogue (sulprostone) in 50 participants and PG E1 analogue (misoprostol) in 194 participantsat a dose of 250 mcg and 800 mcg respectively. The prostaglandins compared with placebo, were not superior in reducing the rate ofmanual removal of placenta (average risk ratio (RR) 0.82; 95% confidence interval (CI) 0.54 to 1.27), severe postpartum haemorrhage(RR 0.80; 95% CI 0.55 to 1.15), need for blood transfusion (RR 0.72; 95% CI 0.43 to 1.22), mean blood loss (mean difference (MD)-205.26 mL; 95% CI -536.31 to 125.79, random-effects) and the mean time from injection to placental removal (MD -7.00 minutes;95% CI -21.20 to 7.20). Side-effects were no different between groups (vomiting, headache, pain and nausea between injection anddischarge from the labour ward), with the exception of shivering, which was more frequent in women receiving prostaglandins (RR10.00; 95% CI 1.40 to 71.49). We did not obtain any data for the primary outcomes of maternal mortality and the need to add anothertherapeutic uterotonic.Authors conclusionsCurrently there is limited, very low-quality evidence relating to the effectiveness and the safety using prostaglandins for the managementof retained placenta. Use of prostaglandins resulted in less need for manual removal of placenta, severe postpartum haemorrhage andblood transfusion but none of the differences reached statistical significance. Much larger, adequately powered studies are needed toconfirm that these clinically important beneficial effects are not just chance findings.Similarly, no differences were detected between prostaglandins and placebo in mean blood loss or the mean time from injection toplacental removal (minutes) or side-effects (vomiting, headache, pain and nausea between injection and discharge from the labourward) except for shivering which was more frequent in women who received prostaglandin. The included studies were of poorquality and there is little confidence in the effect estimates; the true effect is likely to be substantially different. We can not make anyrecommendations about changes to clinical practice. More high-quality research in this area is needed.

PLAIN LANGUAGE SUMMARY

Prostaglandins for management of retained placentaMedical research evidence is sparse and insufficient to support the routine use of the prostaglandins for the management of retainedplacenta.Retained placenta affects 0.5% to 3% of women following delivery and is a major cause of maternal death caused by postpartumhaemorrhage. A retained placenta is usually managed by manual removal or curettage under anaesthesia (which is not always immediatelyavailable). Surgical procedures themselves can be associated with haemorrhage and also infection and uterine perforation. Prostaglandinsor their analogues, administered by any route, could be an alternative treatment especially in developing countries. Such medicalmanagement may facilitate the delivery of the retained placenta and be a safer alternative to surgery.The review identified three randomised controlled studies (involving 244 women) that compared the use of prostaglandins with placebo.Currently there is limited, very low-quality evidence relating to the effectiveness and the safety using prostaglandins for the managementof retained placenta. Use of prostaglandins resulted in less need for manual removal of placenta, severe postpartum haemorrhageand need for blood transfusion but none of the differences reached statistical significance. Much larger, adequately powered studiesare needed to confirm that these clinically important beneficial effects are not just chance findings. Similarly, no differences weredetected between prostaglandins and placebo in mean blood loss or the mean time from injection to placental removal (minutes). Theprostaglandin was administered by intravenous infusion (E2 analogue sulprostone) in one study including 50 women and was orallyor sublingually administered (E1 analogue misoprostol) in the other two studies including 194 women.Shivering was more frequent in women receiving the prostaglandin but there were no clear differences in vomiting, headache, maternalpain or nausea compared with placebo. The trials were small and of poor methodological quality. The quality of evidence is very lowdue to study limitations, inconsistency and imprecise results (few women and outcome events with wide confidence intervals). Twostudies were stopped early due to an apparent benefit.

60 per 1000 43 per 1000

130 per 1000 94 per 1000

Mean blood loss The mean blood loss in The mean blood loss in 244
Objectively or subjec- the control groups was the intervention groups (3 studies) very low1,5,6 tively measured after 0 millilitres was intervention/Mean blood 205.26 lower loss in ML. (536.31 lower to 125.79 Follow-up: 30 to 45 min- higher) utes 4Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.Prostaglandins for management of retained placenta (Review)

Mean time from injec- The mean time from injec- The mean time from injec- 99
tion to placenta removal tion to placenta removal tion to placenta removal (1 study) very low1,6 Mean time from injection in the control groups was in the intervention groups to placenta removal. minutes was Follow-up: 30 to 45 min- 7.0 lower utes (21.2 lower to 7.2 higher)

Maternal pain between Study population RR 0.91 124

injection and discharge (0.43 to 1.96) (2 studies) very low1,3 from labour ward 172 per 1000 157 per 1000 Maternal pain between (74 to 338) injection and discharge from labour ward Low Follow-up: 1 to 24 hours 100 per 1000 91 per 1000 (43 to 196)

High

200 per 1000 182 per 1000

(86 to 392)

Nausea between injec- Study population RR 1.72 124

tion and discharge from (0.15 to 19.41) (2 studies) very low1,2,6 labour ward 34 per 1000 59 per 1000 Nausea between injec- (5 to 669) tion and discharge from labour ward Low Follow-up: 1 to 24 hours 30 per 1000 52 per 1000 (5 to 582)

High

100 per 1000 172 per 1000

(15 to 1000) 5Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.Prostaglandins for management of retained placenta (Review)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;

GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Failure to adherence to intention-to-treat principle. Selective reporting. Stopping early for benefit. 2 Large variation in effect. Confidence intervals overlap.Substantial heterogeneity. 3 Few women and outcome events. Confidence interval include null effect, include appreciable harm or benefit. Not optimal information

size. 4 Lack of blinding. Failure to adherence to intention-to-treat principle. Selective reporting. Stopping early for benefit. 5 Large variation in effect. Confidence intervals do not overlap. Substantial heterogeneity. 6 Few women. Confidence interval includes null effect, include appreciable harm or benefit. Not optimal information size. 6BACKGROUND is limited to the uterine muscle and it is in fact, strictly dependent on calcium concentration (Arias 2000). Prostaglandins E and F are the most important types ofDescription of the condition prostaglandins with uterotonic activity and have a relevant ad- vantage compared with oxytocin in terms of biological activity.Postpartum haemorrhage (PPH) is an important cause of mater- Prostaglandins E and F can be administered, and are absorbed by,nal mortality (Sosa 2009) and it accounts for nearly one quarter of any route including intravenous, oral, sublingual, vaginal or in-all maternal deaths world-wide with an estimated 125,000 deaths tracervical administration with variable incidence of side-effectsper year (Carroli 2008). The overall incidence of PPH is about (Arias 2000). The knowledge that prostaglandins can be delivered6% with wide variations around the world; the highest rates oc- to the retro placental myometrium by any route has stimulated acur in Africa with 10.5%; North America, Europe, Oceania and lot of interest.Latin America have intermediate rates and the lowest rates arefound in Asia (2.6%) (Carroli 2008). PPH is also associated withserious morbidity including the need for blood transfusion, renal How the intervention might workfailure, coagulation de ciencies, anaemia and hysterectomy or Ultrasound studies have improved the understanding of the thirdother surgical procedures with subsequent consequences on fertil- stage of labour. One study (Herman 1993), using ultrasonogra-ity (Bodelon 2009). phy demonstrated that retro placental myometrial contraction isOne of the main causes of PPH is retained placenta, which affects paramount to produce shearing forces on the interface between0.5% to 3.0% of women following delivery, and is a major cause the placenta and myometrium, leading to its detachment. A pro-of maternal death due to PPH. A further 15% to 20% of the longed third stage is due to contractile failure in the retro placen-PPH maternal deaths are due to retained placenta. After uterine tal area (Weeks 2008), with difficulties for occluding the bloodatony, retained placenta is the second major indication for bloodtransfusion in the third stage of labour (Owolabi 2008). Retained ow through the arcuate and radial arteries to the placental frag-placenta is a potentially preventable cause of PPH (Hoveyda 2001). ments with the consequences of retained placenta and PPH (WeeksThere is no consensus about the length of the third stage of labour 2001).after which a placenta should be called retained. In Europe, man- Prostaglandins have a potent uterotonic activity caused by theirual removal of placentae are advised at anytime between 20 min- effect of increasing intracellular calcium and activating myosinutes and over one hour after delivery (Weeks 2008). The choice of light chain kinase. The influx of calcium caused by prostaglandins,timing is a balance between the PPH risk of leaving the placenta however, is probably caused by interaction with calcium chan-in situ, the likelihood of spontaneous delivery and the knowledge nels, which is different from the mechanism of oxytocin (Ariasthat the manual removal itself causes haemorrhage (Rizwan 2009). 2000).The role of prostaglandins in uterine muscle contractionsObservational studies have demonstrated that a third stage longer during labour is well known.than 30 minutes was associated with higher rates of PPH, higher The advantages mentioned above, allow prostaglandins to actrates of blood transfusions and dilatation and curettage, compared specifically at the contractile failure area, stimulating contractionswith a third stage of 30 minutes or less (Deneux-Tharaux 2009). in the retro placental myometrium (Weeks 2008). Medical man-Because there was no increase in these medical complications until agement to facilitate the delivery of the retained placenta withthe third stage exceeded 30 minutes, it is suggested that above this prostaglandins could potentially provide a safer alternative, involv-time an intervention is mandatory (Combs 1991). ing early treatment and reducing the risk of complications.

Description of the intervention Why it is important to do this review

Prostaglandins (PG) are molecules responsible for physiologic re- Usually, the retained placenta has been managed by manual re-actions that act as intermediaries in several processes involved dur- moval or curettage with general anaesthesia (which is not immedi-ing pregnancy including term labour, postpartum involution, and ately available in the majority of cases), and which may be associ-placental-fetal vascular dynamics. Their biosynthesis is limited by ated with haemorrhage, infection and uterine perforation. Medicalthe activity of the enzyme arachidonic acid cyclo-oxygenase, which management to facilitate the delivery of the retained placenta couldcatalyses the transformation of arachidonic acid into prostaglandin be a safer alternative that avoids surgical intervention (Sundaram(Miller 2006). 2009). Nowadays, oxytocin umbilical vein injection and tocolysisProstaglandins receptors are present in both, pregnant and non- have been the medical interventions systematically evaluated forpregnant, uteri and their concentration in the myometrial tissue treating retained placenta with no effect (Nardin 2011) and withincreases at the beginning of labour. Prostaglandins have effects limited evidence available for tocolysis (Abdel-Aleem 2011). Toon the myometrium and cervix, whereas the activity of oxytocin date, no systematic review has examined the role of prostaglandins

Prostaglandins for management of retained placenta (Review) 7

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.for the medical management of retained placenta. Prostaglandins 4. Other pharmacological interventions for management ofor their analogues, administered by any route, could offer theoret- retained placenta.ical advances especially in developing countries. It is important to 5. Non-pharmacological and non-surgical interventions forassess the effectiveness and safety of prostaglandins for the man- managing retained placenta (Mockler 2012).agement of retained placenta. Medical management to facilitate To avoid duplication, each individual Cochrane review on thisthe delivery of the retained placenta with prostaglandins could topic will include comparisons only with the interventions listedpotentially provide a safer alternative involving an earlier treat- above it in the list. Consequently, this review (which is num-ment and reducing the morbidity and mortality associated with ber three in the list) included comparisons of prostaglandin (orthis condition. prostaglandin analogue) (any type, dose, and route except um- bilical vein injection (UVI)) versus any other prostaglandin (or prostaglandin analogue) (any type, dose, and route except UVI), tocolysis (2), surgical management (1) and placebo/expectant management.OBJECTIVES This strategy will avoid the same comparisons being included inTo assess the effectiveness and safety of prostaglandins for the more than one of the original Cochrane reviews. The Cochranemanagement of retained placenta. reviews listed above will not include comparisons with UVI, which is covered in a separate review (Nardin 2011).

METHODS Types of outcome measures

In order to maximise consistency between reviews on the topic of managing retained placenta, a number of core outcomes haveCriteria for considering studies for this review been identified and these were incorporated into all the reviews on this topic.

Types of studies Primary outcomes

All published and unpublished randomised controlled clinical tri- 1. Maternal mortality.als comparing the use of prostaglandins (or prostaglandin ana- 2. Manual removal of the placenta.logues) with placebo, expectant management, tocolytic drugs, any 3. Severe postpartum haemorrhage (defined as clinicallyother prostaglandin or surgical interventions for the management estimated blood loss greater than or equal to 1000 mL).of retained placenta. Quasi-randomised trials, cluster-randomised 4. Blood transfusion.trials and trials using a cross-over design were not included. 5. Need to add other therapeutic uterotonic.

Types of participants Secondary outcomes

All women having a vaginal delivery of singleton live infants of 1. Serious maternal morbidity (hysterectomy, admission to20 or more weeks of gestational age, with a retained placenta, intensive care, renal or respiratory failure, and other additionalregardless of the management of the third stage of labour or the surgical procedures to treat PPH different to manual removal ofhistory of prior caesarean delivery. We defined retained placenta placenta, related to the randomised interventions).as a third stage exceeding 30 minutes after delivery of the infant. 2. Postpartum haemorrhage (PPH) (defined as clinicallyWe excluded studies in which women have a clear diagnosis of estimated or measured blood loss greater than or equal to 500placenta accreta. mL). 3. Maternal postpartum anaemia (defined by the haemoglobin concentration according to local standards).Types of interventions 4. Mean blood loss (mL).There are a number of existing or planned Cochrane reviews on 5. Mean time from injection to placental removal (minutes).the topic of management of retained placenta. The current list 6. Perinatal fall in haemoglobin levels (defined as decrease inincludes the following. previous haemoglobin concentration levels by at least 10%). 1. Surgical management of retained placenta. 7. Need for iron tablets during the puerperium. 2. Tocolysis for management of retained placenta 8. Subsequent surgical evacuation of retained products of(Abdel-Aleem 2011). conception. 3. Prostaglandins for management of retained placenta (this 9. Diastolic blood pressure greater than 100 mmHg betweenreview). injection and discharge from the labour ward.

Prostaglandins for management of retained placenta (Review) 8

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 10. Vomiting between injection and discharge from the labour 3) for conference proceedings, dissertations and theses and open-ward. SIGLE (1997 to 1 December 2013) (Appendix 4) for grey litera- 11. Shivering between injection and discharge from the labour ture.ward. We searched the World Health Organization International Clin- 12. Nausea between injection and discharge from the labour ical Trials Registry Platform (ICTRP) (1 December 2013) (ward. Appendix 5) and the metaRegister of Controlled Trials (mRCT) 13. Headache between injection and discharge from the labour (1 December 2013) (Appendix 6) for ongoing studies.ward. 14. Maternal pain between injection and discharge from the Searching other resourceslabour ward. 15. Maternal dissatisfaction with third stage management. We contacted the first author of the included studies and sent a 16. Secondary PPH (after 24 hours and before six weeks). comprehensive list of relevant articles along with the inclusion cri- 17. Bleeding needing readmission. teria for the review, asking for any additional studies published or 18. Need for treatment with antibiotics. unpublished which might be relevant. Additionally, we searched 19. Maternal fatigue. the citation lists from reviewed articles and other relevant publi- 20. Breastfeeding at discharge from hospital. cations. We did not apply any language restrictions.

Search methods for identification of studies

Data collection and analysis

Electronic searches Selection of studiesWe contacted the Trials Search Co-ordinator to search the Two review authors independently assessed for inclusion all theCochrane Pregnancy and Childbirth Groups Trials Register (1 potential titles and abstracts of studies retrieved as a result of theDecember 2013). search strategy to reduce the possibility that relevant reports wereThe Cochrane Pregnancy and Childbirth Groups Trials Register discarded. The review authors were masked to information of theis maintained by the Trials Search Co-ordinator and contains trials article such as journal title, authors, institutions, magnitude andidentified from: direction of the results. Any disagreement was resolved through 1. monthly searches of the Cochrane Central Register of consensus or, if required, by consulting a third review author.Controlled Trials (CENTRAL); We retrieved the full text of an article if there was any doubt as to 2. weekly searches of MEDLINE; whether the article should be included or excluded. 3. weekly searches of Embase; 4. handsearches of 30 journals and the proceedings of majorconferences; Data extraction and management 5. weekly current awareness alerts for a further 44 journals We designed a form to extract data. For eligible studies, two re-plus monthly BioMed Central email alerts. view authors extracted data independently using the agreed form;Details of the search strategies for CENTRAL, MEDLINE and those review authors were thematic and methodological experts.Embase, the list of handsearched journals and conference pro- Discrepancies were resolved through consensus or, if required, byceedings, and the list of journals reviewed via the current aware- consulting a third review author.ness service can be found in the Specialized Register section The data extracted included the following.within the editorial information about the Cochrane Pregnancyand Childbirth Group.Trials identified through the searching activities described above Methodsare each assigned to a review topic (or topics). The Trials Search Location of the study. Setting.Co-ordinator searches the register for each review using the topic Trial design.list rather than keywords. Power calculation performed.In addition, we searched regional databases because they could be Method used to generate random allocation.an important source of additional studies from journals not in- Methods used to maintain allocation concealment.dexed in other international databases Castro 2002. These were: Number of women enrolled, randomised, excluded afterLILACS (1982 to 1 December 2013) Castro 1999 (Appendix randomisation, and analysed.1) and SciELO (1998 to 1 December 2013) (Appendix 2). We Use of any method of blinding of the researchers to thesearched Web of Science (2001 to 1 December 2013) (Appendix intervention in order to evaluate outcomes.

Prostaglandins for management of retained placenta (Review) 9

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Number of participants lost to follow-up in the groups. The methodology was assessed as: Use of intention-to-treat analysis. low risk of bias (any truly random process, e.g. random Funding sources, reported. number table; computer random number generator); Ethical issues: use of signed informed consent and ethics high risk of bias (any non-random process, e.g. odd or evenapproval. date of birth; hospital or clinic record number); unclear risk of bias (insufficient information about theParticipants sequence generation process to permit judgement of low or high). Inclusion and exclusion criteria. Baseline information on the participants in order to havecomparable intervention and control groups at entry (2) Allocation concealment (checking for possible selection(management of the third stage of labour, retained placenta bias)definition, exclusion of women with a clear diagnosis of placenta We described for each included study the method used to concealaccreta). allocation to interventions prior to assignment and we assessed whether intervention allocation could have been foreseen in ad-Interventions vance of, or during recruitment, or changed after assignment. We assessed the methods as: Total number of intervention groups. low risk of bias (e.g. telephone or central randomisation; Types of interventions: prostaglandins (or analogues) types, consecutively numbered sealed opaque envelopes);doses, route of administration a duration intervention. high risk of bias (open random allocation; unsealed or non- Adherence to planned intervention and other interventions opaque envelopes, alternation; date of birth);in the groups under evaluation. unclear risk of bias.

Outcomes (3.1) Blinding of participants and personnel (checking for Outcomes stated in methods versus outcomes reported in possible performance bias)results. We described for each included study the methods used, if any, to How secondary outcomes were de ned. blind study participants and personnel from knowledge of which Differences between groups for outcome assessment. intervention a participant received. We considered that studies Time of follow-up of participants to measure outcomes. were at low risk of bias if they were blinded, or if we judged that How adverse event reports were validated. the lack of blinding would be unlikely to affect results. We assessedThis information was collated and presented in the tables blinding separately for different outcomes or classes of outcomes.Characteristics of included studies and Characteristics of excluded We assessed the methods as:studies. Data were entered into Review Manager (RevMan 2012) low, high or unclear risk of bias for participants;and checked for accuracy. When information regarding any of the low, high or unclear risk of bias for personnel.above was unclear, we contacted authors of the original reports toprovide further details. (3.2) Blinding of outcome assessment (checking for possible detection bias)Assessment of risk of bias in included studies We described for each included study the methods used, if any, toTwo review authors independently assessed risk of bias for each blind outcome assessors from knowledge of which intervention astudy using the criteria outlined in the Cochrane Handbook for participant received. We assessed blinding separately for differentSystematic Reviews of Interventions (Higgins 2011). Any disagree- outcomes or classes of outcomes.ment was resolved by consensus or by involving a third assessor We assessed the methods used to blind outcome assessment as:when necessary. Review authors who assessed the risk of bias were low, high or unclear risk of bias.blinded to the names of authors, institutions, journals and resultsof studies and were theme and methodology experts. (4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete(1) Random sequence generation (checking for possible outcome data)selection bias) We described for each included study, and for each outcome orWe described for each included study the method used to generate class of outcomes, the completeness of data including attritionthe allocation sequence in sufficient detail to allow an assessment and exclusions from the analysis. We stated whether attrition andof whether it should produce comparable groups. exclusions were reported and the numbers included in the analysis

Prostaglandins for management of retained placenta (Review) 10

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.at each stage (compared with the total randomised participants), if We used the GRADE approach in order to produce a Summary ofreasons for attrition or exclusion were reported, and whether miss- findings table. We downgraded the quality of evidence dependinging data were balanced across groups or were related to outcomes. on the presence of the following factors.Where sufficient information was reported, or could be supplied Downgrade quality level for:by the trial authors, we planned to re-included missing data in the 1. study limitations;analyses which we undertook. 2. inconsistency of results;We assessed methods as: 3. indirectness of evidence; low risk of bias (e.g. no missing outcome data; missing 4. imprecision;outcome data balanced across groups); 5. publication bias. high risk of bias (e.g. numbers or reasons for missing dataimbalanced across groups; as treated analysis done with Measures of treatment effectsubstantial departure of intervention received from that assignedat randomisation); unclear risk of bias. Dichotomous dataWe used a cut-off point of 20% to consider that a study was at For dichotomous data, results are presented as summary risk ratiolow or high risk of bias according to the level of missing data. (RR) with 95% confidence intervals (CI).The RR like the relative effect measure has consistency, works well with low or high rates of events and it is easier to interpret in clinical practice.(5) Selective reporting (checking for reporting bias)We described for each included study how the possibility of selec-tive outcome reporting bias was investigated and what we found. Continuous dataWe assessed the methods as: For continuous data, we used the mean difference (MD) as out- low risk of bias (where it was clear that all of the studys pre- comes were measured in the same way between trials. If necessary,specified outcomes and all expected outcomes of interest to the we would have used the standardised mean difference (SMD) toreview had been reported); combine trials that measured the same outcome, but used differ- high risk of bias (where not all the studys pre-specified ent methods.outcomes had been reported; one or more reported primaryoutcomes were not pre-specified; outcomes of interest were Unit of analysis issuesreported incompletely and so could not be used; study failed toinclude results of a key outcome that would have been expectedto have been reported); Other unit of analysis issues unclear risk of bias. In future updates of this review, if we identify a clinical trial in which participants are randomised to several intervention groups,(6) Other bias (checking for bias due to problems not we will determine which intervention groups are relevant and tocovered by (1) to (5) above) avoid confusion for the reader, we will report all interventionWe described for each included study any important concerns we groups of the study in the table of Characteristics of includedhad about other possible sources of bias. studies in the notes cell, as well as we will provide a detailed de-We assessed whether each study was free of other problems that scription of the intervention groups relevant to the review andcould cause risk of bias: only use these groups in our analyses. In order to avoid a unit- low risk of other bias; of-analysis error for a study that could contribute multiple, corre- high risk of other bias; lated, comparisons, we will combine groups to create a single pair- unclear whether there is risk of other bias. wise comparison.

(7) Overall risk of bias Dealing with missing data

We made explicit judgements about whether studies were at high For included studies, we noted levels of attrition. We plannedrisk of bias, according to the criteria given in the Handbook ( to investigate the impact of including studies with high levels ofHiggins 2011). With reference to (1) to (6) above, we assessed the missing data in the overall assessment of treatment effect by usingmagnitude and direction of the bias and whether we considered sensitivity analysis if high-quality studies were included in theit was likely to impact on the findings. We explored the impact meta-analysis. For all outcomes, we carried out analyses, as farof the level of bias through undertaking sensitivity analyses - see as possible, on an intention-to-treat basis, i.e. we attempted toSensitivity analysis. include all participants randomised to each group in the analyses,

Prostaglandins for management of retained placenta (Review) 11

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.and all participants were analysed in the group to which they were We planned the following subgroup analyses:allocated, regardless of whether or not they received the allocated 1. comparison of different prostaglandin type;intervention. The denominator for each outcome in each trial was 2. comparison of different prostaglandin administration route;the number randomised minus any participants whose outcomes 3. comparison of the time to intervention administration (lesswere known to be missing. than 60 minutes; 60 minutes or more). We planned to restricted subgroup analyses to the primary out- come: need for manual removal of placenta.Assessment of heterogeneity For fixed-effect inverse variance meta-analyses, we assessed differ-We assessed statistical heterogeneity in each meta-analysis using ences between subgroups by interaction tests. For random-effectsthe T, I and Chi statistics. We regarded heterogeneity as sub- and fixed-effect meta-analyses using methods other than inversestantial if the I was greater than 30% and either the T was greater variance, we assessed differences between subgroups by inspec-than zero, or there was a low P value (less than 0.10) in the Chi tion of the subgroups confidence intervals; non-overlapping con-test for heterogeneity. Where we identified substantial heterogene- fidence intervals indicated a statistically significant difference inity, we explored it by pre-specified subgroup analysis. treatment effect between the subgroups.

Assessment of reporting biases Sensitivity analysis

In future updates of this review, if there are 10 or more studies We planned sensitivity analyses according to used definition ofin the meta-analysis we will investigate reporting biases (such as prolonged third stage (less than 60 minutes; 60 minutes or more)publication bias) using funnel plots. We will assess funnel plot and to explore the effects of xed-effect or random-effects analysisasymmetry visually. If asymmetry is suggested by a visual assess- for outcomes with statistical heterogeneity. In future updates ofment, we will perform exploratory analyses to investigate it. this review, we will carry out sensitivity analyses for others aspects of the review that also might affect the results, such as the riskData synthesis of bias associated with the quality of the included trials based on overall Risk of bias assessment (low versus unclear and high riskWe carried out statistical analysis using the Review Manager of bias).(RevMan 2012). We used fixed-effect meta-analysis for combin-ing data when it was reasonable to assume that studies were esti-mating the same underlying treatment effect: i.e. where trials wereexamining the same intervention, and the trials populations andmethods were judged sufficiently similar. We used random-effects RESULTSmeta-analysis if there were clinical heterogeneity sufficient to ex-pect that the underlying treatment effects differed between trials,or if substantial statistical heterogeneity was detected, to produce Description of studiesan overall summary, if an average treatment effect across trials wasconsidered clinically meaningful. The random-effects summarywas treated as the average range of possible treatment effects and Results of the searchwe discussed the clinical implications of treatment effects differing A total of 1038 references were retrieved and reviewed after dupli-between trials. If the average treatment effect was not clinically cation. Of these, nine were initially screened as randomised con-meaningful, we did not combine trials. trolled trials (RCTs). Three studies that met the inclusion criteria were identified (See Figure 1). The included studies (van Beekhuizen 2006; van StralenSubgroup analysis and investigation of heterogeneity 2013; van Beekhuizen 2013) were published manuscripts. WeWe planned to undertake subgroup analyses and sensitivity anal- excluded six studies (Habek 2007; Harara 2011; Notten 2012;yses if we identified substantial heterogeneity. Paavonen 2012; Rogers 2007; Sundaram 2007).

Prostaglandins for management of retained placenta (Review) 12

Prostaglandins for management of retained placenta (Review) 13

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. minutes the other two. The limit time for manual removal of theIncluded studies placenta was 30 minutes in two studies (van Beekhuizen 2006; vanThe three studies had small sample sizes and included a total Beekhuizen 2013) and 45 minutes in the other one (van Stralenof 244 women; the largest trial included 99 participants (van 2013).Stralen 2013). One study (van Beekhuizen 2006) was developedin two phases, the first one was a randomised phase comparingprostaglandin with placebo; and the second one had a non-ran- Outcomesdomised assignation to the branch of prostaglandin. In order tocarry out the analysis planned in our a priori protocol, we just Although the included studies reported at least one prespecifiedincluded the randomised phase results with 50 participants. The primary outcome of this review, there were some differences instudies were from The Netherlands and Tanzania and were pub- reporting and de nition of the outcomes. The trials recorded thelished in English. need of manual removal of the placenta, blood transfusion, mean blood loss (mL), nausea and maternal pain between injection, dis-Population charge from the labour ward and severe postpartum haemorrhage. One study (van Stralen 2013) also registered mean time from in-The three studies included 244 participants (PG E2 analogue sul- jection to placental removal (minutes), vomiting, shivering andprostone with 50 participants and PG E1 analogue misoprostol headache between injection and discharge from the labour ward.with 194 participants), were multicentric and recruited womenwho were admitted for hospital delivery or who had home deliv-ery. Two studies (van Beekhuizen 2006; van Beekhuizen 2013)included pregnancies with gestational age 28 weeks and the Length of follow-upother one (van Stralen 2013) included pregnancies with at least The women were followed up for 12 to 24 hours (van Beekhuizen25 completed weeks of pregnancy. The studies included women 2013) and from six to eight weeks postpartum (van Stralen 2013).having singleton pregnancy regardless of parity or previous history In the third study (van Beekhuizen 2006), the timing of follow-of manual removal of placenta or caesarean delivery. One study up was not specified.(van Beekhuizen 2006) included six women who received the in-tervention after operative vaginal delivery and 25 women witha previous history of curettage. van Stralen 2013 also included Excluded studiessix women with history of postpartum haemorrhage (PPH). Thethird study (van Beekhuizen 2013) did not mention the character- Six studies were excluded for the following reasons: four studiesistics of the included women. During delivery, all women received were not RCTs and two studies included a different interventionactive management of labour with oxytocin in two studies (van (Intra-umbilical route). See Characteristics of excluded studies.Beekhuizen 2006; van Beekhuizen 2013), but this interventionwas not mentioned in the other one (van Stralen 2013). Risk of bias in included studies

InterventionsOne study (van Beekhuizen 2006) compared PG E2 analogue Allocation(sulprostone) at a single doses of 250 mcg by 30 minutes of in-travenous infusion with placebo (saline solution) and included 50 Two trials (van Beekhuizen 2006; van Beekhuizen 2013) ade-women. The other two (van Beekhuizen 2013; van Stralen 2013) quately reported the method of random generation as using a com-compared PG E1 analogue (misoprostol) with placebo at a single puter-generated randomisation list, and the concealment of allo-doses of 800 mcg administered orally dissolved in water or sub- cation method by using sequentially numbered sealed envelopes,lingually administrated and included 194 women. making selection bias at entry unlikely. The other trial (van Stralen 2013), did not report the method of random generation used but, based on the information provided during correspondence withTime to intervention administration and time limit for the author, they implemented a computer-generated randomisa-manual removal of the placenta tion list and sequentially numbered drugs containers, also makingThe time to intervention administration after delivery of the new- selection bias at entry unlikely. We judged all three studies to beborn was 30 minutes in one study (van Beekhuizen 2013) and 60 at low risk of bias for selection bias.

Prostaglandins for management of retained placenta (Review) 14

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.Blinding criteria used to defined the outcome and it was measured during puerperium. Because blinding was broken after randomisation toOne study (van Beekhuizen 2006), did not adequately report the some women according to the obstetrician judgment during themethod implemented to blind study participants, outcome asses- postpartum stage, some clinicians could have had knowledge aboutsor and personnel from knowledge of which intervention a par- the womens intervention. No blinding or incomplete blinding,ticipant received. We contacted the principal author to obtain the and the way the outcome was measured makes detection bias likely.necessary information for this judgment. Because the blinding Finally, the third study (van Beekhuizen 2013) implemented amethod was reported as The physician in charge was blinded technique of over encapsulation for both the 800 g misoprostolto the trial medication we assessed the risk of detection bias tablets and the placebo tablets so that all tablets were the same size,separately for each outcome. and the placebo had a bitter taste and was dissolved sublinguallyManual removal of placenta was objectively assessed and this out- similar to misoprostol. Because the method implemented to blindcome was measured during delivery. The blinding of participants study participants and personnel from knowledge of which inter-and key study personnel was ensured and it was unlikely that there vention a participant received, we assessed as unlikely the risk ofwas detection bias. A time limit of 30 minutes for manual removal performance and detection bias.of placenta was established, in an effort to diminish the risk of per-formance bias. The outcomes pain and nausea were subjectivelyassessed but it was unclear when theses outcomes were measured. Incomplete outcome dataThe method implemented in order to blind participants and keystudy personnel was not adequately reported, making an unclear In one included trial (van Beekhuizen 2006), 15.2% of the womenthe risk of bias. were excluded from the analysis for violations of the treatmentBlood loss (measured in mL) was assessed objectively for women protocol. One woman withdrew her consent; one women men-admitted for hospital delivery (determined by weight) and sub- tioned after inclusion that she had a cardiac condition that wasjectively for women who had home delivery (estimated by the re- a contraindication to participate in the study; in three women,ferring midwife). The method implemented in order to blind the the placenta was expelled within 60 minutes after delivery of theparticipants and key study personnel was not adequately reported, infant before trial medication, and in four women, blood loss ex-which we considered resulted in an unclear the risk of bias. For ceeded 1000 mL before medication; the authors carried out anblood transfusion and side-effects such as pain and nausea, the as-treated analysis because they only included the results fromauthor did not mention the method implemented to blind partic- those women who had both been assigned randomly and who hadipants and key study personnel, making unclear the risk of bias. actually received the trial medication making attrition bias likely.In van Stralen 2013, the pills containing the interventions were In another study (van Stralen 2013), follow-up data were availableidentical and placed in identical containers in order to blind study for 38 (78%) women in the misoprostol group and 44 (86%)participants and personnel from knowledge of which intervention women in the placebo group. Follow-up for the outcomes: manuala participant received, and a time limit of 45 minutes for manual removal of the placenta, blood transfusion and severe postpartumremoval of placenta was established, in an effort to diminish the haemorrhage were completed with just one loss, but the follow-uprisk of performance bias. Because blinding was broken after ran- data for side-effects such as vomiting, shivering, nausea, headachedomisation to some women for breastfeeding reasons during the and pain were incomplete with more than 20% missing data. Nopostpartum stage, we assessed the risk of detection bias separately explanation for these losses to follow-up were provided, leading tofor each outcome. a high risk of attrition bias for.Outcomes such as manual removal of placenta, severe postpartum In the remaining trial (van Beekhuizen 2013), two women werehaemorrhage, mean blood loss (measured in mL, estimated by excluded from the analysis because of follow-up loss, one in eachcollecting and weighing all blood, including in swabs and drapes) arm. Because the proportion of missing data compared with ob-and mean time from injection to placental removal (minutes) were served event risk was not enough to have a clinically relevant im-objectively assessed and these outcomes were measured during pact of the intervention effect estimate, we assessed this as beingdelivery. Blinding of participants and key study personnel was an unlikely the risk of attrition bias.ensured and it was unlikely that blinding could have been broken,making detection bias improbable. Outcomes such as vomiting,shivering, nausea, headache and maternal pain between injection Selective reportingand discharge from the labour ward were subjectively assessed and In one study (van Beekhuizen 2006). the study protocol is notthese outcomes were measured during the first two hours after the available and it is unclear if the published reports included allintervention. Blinding of participants and key study personnel was expected outcomes, including those that were prespecified. Theensured and it was unlikely that blinding could have been broken, report did not have sufficient information to permit judgment ofthus making detection bias unlikely. Yes or No (rated as unclear risk of bias). For the remaining tri-For need for blood transfusion, the author did not mention any als, outcomes such as blood transfusion, PPH and haemoglobin at

Prostaglandins for management of retained placenta (Review) 15

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.discharge from hospital were not pre specified in the protocol (IS-RCTN16104753 (van Beekhuizen 2013) and ISRCTN45330307(van Stralen 2013)), but were reported during the publication,thus raising the issue of reporting bias.

Other potential sources of bias

Two studies (van Beekhuizen 2006; van Beekhuizen 2013) had apotential source of bias related to a formal stopped early rule dueto apparent benefit; the other study (van Stralen 2013) appears tobe free from other sources of bias.In summary, according to the criteria applied for the sensitivityanalysis, the trials were of poor methodological quality or therewas insufficient information for inclusion into the high-qualitygroup (Figure 2; Figure 3).

Figure 2. Risk of bias graph: review authors judgements about each risk of bias item presented as percentages across all included studies.

Prostaglandins for management of retained placenta (Review) 16

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Figure 3. Risk of bias summary: review authors judgements about each risk of bias item for each included study.

Prostaglandins for management of retained placenta (Review) 17

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. group and the placebo group in the mean blood loss (mean dif-Effects of interventions ference (MD) -205.26 mL; 95% CI -536.31 to 125.79, three tri-See: Summary of findings for the main comparison als, 244 women, random-effects, Tau = 63417.09, I2 = 75%)prostaglandins for retained placenta (Analysis 1.4).Overall, we included three trials, involving a total of 244 women.We carried out a total of six meta-analysis (more than one trialanalysed) and four comparisons correspond to a single-trial anal- Mean time from injection to placental removalysis. (minutes)To display outcomes that were investigated only in single studies, We reported results corresponding to a single-trial analysis (vanwe used a single forest plot in order to summarise the information Stralen 2013). There was no significant difference in the mean(Higgins 2011). time from injection to placental removal (MD -7.00 minutes; 95% CI -21.20 to 7.20; one trial, 99 participants) (Analysis 1.5).Prostaglandins versus placebo (primary outcomes)

Vomiting between injection and discharge from the

Manual removal of placenta labour wardThe following results correspond to the meta-analysis of all The following result corresponds to a single-trial analysis (vanthree studies (van Beekhuizen 2006; van Beekhuizen 2013; van Stralen 2013). There was no significant difference in the rate ofStralen 2013). There was no significant difference between the vomiting between injection and discharge from the labour wardprostaglandins and the placebo group in the rate of manual re- (RR 5.37, 95% CI 0.29 to 100.43; one trial, 74 participants)moval of placenta (average risk ratio (RR) 0.82, 95% confidence (Analysis 1.6).interval (CI) 0.54 to 1.27; three trials, 244 women, Tau = 0.09,I = 60%) (Analysis 1.1). Shivering between injection and discharge from the labour wardSevere postpartum haemorrhage We reported results corresponding to a single-trial analysis (vanWe reported results corresponding to the meta-analysis of two Stralen 2013). There was a significant difference favouring placebostudies (van Beekhuizen 2013; van Stralen 2013). There was no in the rate of shivering between injection and discharge from thesignificant difference in the rate of severe postpartum haemorrhage labour ward (RR 10.00, 95% CI 1.40 to 71.49; one trial, 70(RR 0.80, 95% CI 0.55 to 1.15; two trials, 194 participants; I2 = participants) (Analysis 1.7).0%) (Analysis 1.2).

Nausea between injection and discharge from the

Blood transfusion labour wardThis following results correspond to the meta-analysis of three The following results correspond to meta-analysis of two studiesstudies (van Beekhuizen 2006; van Beekhuizen 2013; van (van Beekhuizen 2006; van Stralen 2013). There was no significantStralen 2013). There was no significant difference between the difference between the prostaglandin group and the placebo groupprostaglandin group and the placebo group in the rate of blood in the rate of nausea between injection and discharge from thetransfusion (RR 0.72, 95% CI 0.43 to 1.22; three trials, 244 labour ward (average RR 1.72, 95% CI 0.15 to 19.41; two trials,women, I2 = 0%) (Analysis 1.3). 124 women, Tau = 1.38, I = 43%) (Analysis 1.8).

Prostaglandins versus placebo (secondary outcomes) Headache between injection and discharge from the labour ward We reported results corresponding to a single-trial analysis (vanMean blood loss (mL) Stralen 2013). There was no significant difference in the rate ofThe following results correspond to meta-analysis of three studies headache between injection and discharge from the labour ward(van Beekhuizen 2006; van Beekhuizen 2013; van Stralen 2013). (RR 0.76, 95% CI 0.05 to 11.72; one trial, 74 participants) (There was no significant difference between the prostaglandin Analysis 1.9).

Prostaglandins for management of retained placenta (Review) 18

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.Maternal pain between injection and discharge from to confirm that these clinically important beneficial effects are notthe labour ward just chance findings.The reported results corresponding to meta-analysis of two studies Similarly, no differences were detected between prostaglandins and(van Beekhuizen 2006; van Stralen 2013). There was no signifi- placebo in mean blood loss or the mean time from injection tocant difference in the rate of maternal pain between injection and placental removal (minutes) or side-effects (vomiting, headache,discharge from the labour ward (RR 0.91, 95% CI 0.43 to 1.96; pain and nausea between injection and discharge from the labourtwo trials, 124 participants; I2 = 0%) (Analysis 1.10). ward) except for shivering which was more frequent in women who received prostaglandin. For the primary outcomes maternal mortality and need to add other therapeutic uterotonic, we didSubgroup analysis and investigation of heterogeneity not obtain any data.Subgroup analyses were carried out comparing the differentprostaglandin type, the administration route and the time to in-tervention. The subgroup analyses were restricted to the primary Overall completeness and applicability ofoutcome: need for manual removal of placenta according to the evidenceprotocol. Although comprehensive searches were conducted in order to re-When we explored the heterogeneity source by prostaglandin type trieve all published and unpublished randomised clinical trials,(Analysis 2.1), the interaction test for subgroup differences was this systematic review included only three trials of poor method-statistically significant (P = 0.04). For the subgroup relating to E2 ological quality and with small sample sizes. Additionally, the dataprostaglandin (sulprostone), the rate of manual removal of pla- are incomplete, and some of important clinical outcomes were notcenta was significantly minor for the intervention group (RR 0.54, reported. For example, none of the included studies assessed the in-95% CI 0.34 to 0.86; one trial, 50 women) contrasting with the cidence of maternal mortality, need to add other therapeutic utero-E1 prostaglandin (misoprostol) subgroup, where the intervention tonics, serious maternal morbidity, maternal postpartum anaemiadid not show a significant difference (average RR 0.99, 95% CI or maternal satisfaction with treatment. There were also no com-0.72 to 1.36; two trials, 194 participants, I2 = 0%) compared with parisons between the medical management with prostaglandin andplacebo. usual care. Consequently, the effectiveness and safety of medicalThe tests for subgroup effect by administration route (intravenous management with prostaglandin compared with manual removalinfusion, oral and sublingual) (Analysis 3.1) and by the time to of retained placenta, is still unknown.intervention administration (less than 60 minutes versus 60 min- The applicability of the evidence outside the research setting isutes or more) (Analysis 4.1) were not statistically significant. limited; however, these studies were all conducted in similar clin- ical settings and included a variety of clinical situations. Of theSensitivity analysis interventions analysed in the review, the PG E1 analogue (miso- prostol) is the only prostaglandin that may be available in differentWe could not carry out the planned sensitivity analyses based clinical settings; contrasting with the PG E2 analogue (sulpros-on the quality of the included trials because all of the included tone), which is expensive, and requires refrigeration; as a result, itstudies were assessed as having a high risk of bias. Our sensitivity is not affordable in developing countries.analyses based on the definition of prolonged third stage (less than60 minutes; 60 minutes or more) showed the same result as thatobtained for the time to intervention subgroup analysis. Quality of the evidence The three included studies were judged to be at a high risk of bias and the evidence quality is considered to be very low (SummaryDISCUSSION of findings for the main comparison). There is little confidence in the effect estimates; the true effect is likely to be substantially different. The quality of evidence is very low due to study limita- tions (lack of blinding, failure to adhere to the intention-to-treatSummary of main results principle, selective reporting and stopping early due to apparentWe included three studies (involving 244 women) comparing the benefit), inconsistency (unexplained variability in some results)use of prostaglandins versus placebo for the management of re- and imprecise results (few women and outcome events with widetained placenta. Use of prostaglandins resulted in less need for confidence intervals).manual removal of placenta, severe postpartum haemorrhage and We could not evaluate publication bias, because there were tooblood transfusion but none of the differences reached statistical few included studies and the trials were small. There remains somesignificance. Much larger, adequately powered studies are needed concern about publication bias.

Prostaglandins for management of retained placenta (Review) 19

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.Potential biases in the review process quality and there is little confidence in the effect estimates; the true effect is likely to be substantially different. We can not make anyPublication bias is a possibility in this review because of the limited recommendations about changes to clinical practice. More high-number of studies and the small sample sizes. It is known that the quality research in this area is needed.risk of publication bias is probably higher for reviews that are basedon small trials. Another important limitation of this systematicreview is the measurement bias present in the available studies, Implications for researchespecially when the outcomes were assessed subjectively. Finally, There is an urgent need for high-quality randomised controlledthere was substantial heterogeneity for some outcomes and our trials on treatments for women with retained placenta, particu-investigation of heterogeneity sources (which was based on three larly comparing manual removal and medical treatment includingstudies) has limited value. prostaglandins. Further research should focus on avoiding risk of bias such as, lack of blinding, failure to adhere to the intention-to- treat principle, selective reporting and stopping early for apparent benefit. Future studies should report important clinical outcomesAUTHORS CONCLUSIONS such as: maternal mortality, the need to add another therapeutic uterotonic, the presence of serious maternal morbidity, the fre-Implications for practice quency of maternal postpartum anaemia or subsequent surgical evacuation of retained products of conception inter alia.Currently there is limited, low-quality evidence relating to the ef-fectiveness and safety of using prostaglandins for the managementof retained placenta. Use of prostaglandins resulted in less need formanual removal of placenta, severe postpartum haemorrhage andblood transfusion but none of the differences reached statistical ACKNOWLEDGEMENTSsignificance. Much larger, adequately powered studies are neededto confirm that these clinically important beneficial effects are not We would like to thank Dr MY Martnez-Velsquez and Dr Ajust chance findings. Bautista-Charry for their participation and clinical perspective during the production of this systematic review.Similarly, no differences were detected between prostaglandins andplacebo in mean blood loss or the mean time from injection to As part of the pre-publication editorial process, this review hasplacental removal (in minutes) or side-effects (vomiting, headache, been commented on by four peers (an editor and three refereespain and nausea between injection and discharge from the labour who are external to the editorial team), a member of the Pregnancyward) except for shivering, which was more frequent in women and Childbirth Groups international panel of consumers and thewho received prostaglandin. The included studies were of poor Groups Statistical Adviser.

Study participants were recruited from women who were admitted for hospital delivery and from women who had been referred because of retained placenta after home delivery

Women who were delivered in the hospital all received active management of labour with oxytocin 10 IU intramuscularly, and controlled cord traction. The women who were referred because of retained placenta after home delivery received the same treatment after they had arrived in the hospital. The administration of study medication started 60 minutes after the delivery of the Infant

Prostaglandins for management of retained placenta (Review) 23

The secondary outcome variable was the amount of blood loss (mL). The amount of in-hospital blood loss was determined by weight; blood loss before entering the hospital was estimated by the referring midwife. Adverse event reports (shivering, headache, pain, vomiting and nausea, hypotension and hypertension) were recorded and measured subjectively

Notes Correspondence: yes. We send a letter asking to the principal author about the method implemented in the study in order to blind the study participants and personnel. We used an open question

The author answered: The RCT was double blinded: After the patient was recruited a sealed enveloped was handed to an independent midwife who was not involved in taking care of the patient. She opened the envelope and prepared the study medication and handed the blinded study medication to the midwife/nurse who took care of the patient. This was to ensure that both the patient, the doctor and the midwife were not aware whether the patient received placebo or study medication Comment: unclear risk for performance and detection bias.

Bias Authors judgement Support for judgement

Allocation concealment (selection bias) Low risk the allocation of sealed envelopes was in the sequence of enrolment Comment: probably done

Blinding of participants and personnel Unclear risk Did not adequately reported the method(performance bias) implemented to blind study participantsAll outcomes and personnel from knowledge of which intervention a participant received The physician in charge was blinded to the trial medication Comment: unclear risk of bias

Blinding of outcome assessment (detection Unclear risk Did not adequately reported the methodbias) implemented to blind study participantsAll outcomes and personnel from knowledge of which intervention a participant received The physician in charge was blinded to the trial medication Comment: unclear risk of bias

Incomplete outcome data (attrition bias) High risk Authors did a As-treated analysis becauseAll outcomes they only included the results from those women who had both been assigned ran-

van Beekhuizen 2013

Funding sources, reported: yes. The trial was supported through the Stimuleringsfonds of the Dutch Society of Tropical Medicine and the German Gesellschaft fr Interna- tionale Zusammenarbeitung

Ethical issues: use of signed informed consent and ethics approval

Participants Inclusion and exclusion criteria

Inclusion criteria: Delivered of a baby of 1 kg or more or at a gestational age of 28 weeks or more Exclusion criteria: Haemoglobin concentration less than 100 g/L (6.2 mmol/l). Blood loss more than 750 mL. Pulse rate more than 120 beats per minute. Diastolic blood pressure reduction after delivery more than 20 mmHg Study participants were recruited from women who were admitted for hospital delivery Women who were delivered in the hospital received all active management of labour with oxytocin 5 IU and controlled cord traction

Blinding of participants and personnel Low risk A technique of over encapsulation was(performance bias) used for both the 800-g misoprostolAll outcomes tablets and the placebo tablets. All tablets were the same size, and the placebo had a bitter taste and dissolved sublingually sim- ilar to misoprostol. Comment: probably done

Blinding of outcome assessment (detection Low risk A technique of over encapsulation wasbias) used for both the 800-g misoprostolAll outcomes tablets and the placebo tablets. All tablets were the same size, and the placebo had a bitter taste and dissolved sublingually sim- ilar to misoprostol. Comment: probably done

Incomplete outcome data (attrition bias) Low risk Follow-up data were available for 65/All outcomes 66women in the misoprostol group and 30/ 31 women in the placebo group

Selective reporting (reporting bias) High risk Postpartum haemorrhage (>1 L) and hae- moglobin at discharge from hospital (g/ dL) were not pre specified in the proto- col stage (ISRCTN16104753) but were re- ported during the publication

Ethical issues: use of signed informed consent and ethics approval

Prostaglandins for management of retained placenta (Review) 26

Participants Inclusion and exclusion criteria

Inclusion criteria: Absence of excessive blood loss (as judged by the attending obstetrician) At least 25 completed pregnancy weeks. Minimum participation age was 18 years. Fluent in the Dutch language in word and script.

Exclusion criteria: Postpartum haemorrhage, defined as more than 1000 mL within 60 minutes after birth of the newborn

Study participants were recruited from women who were admitted for hospital delivery and from women who had been referred because of retained placenta after home delivery

Active management of labour: not mentioned.

Interventions Total number of intervention groups: 2 groups.

Intervention: misoprostol 800 g dissolved in water administered orally to the mother.

Single doses. 48 participants Control: placebo dissolved in water administered orally to the mother. Single doses. 51 participants

Outcomes Primary outcome was number of manual removals.

The secondary outcomes were amount of blood loss, blood transfusion, postpartum haemorrhage, interval between delivery of the baby and delivery of the placenta and side- effects of the study medication. The blood loss was measured collecting and weighing all blood, including in swabs and drapes

Notes Correspondence: yes. We send a letter asking to the principal author about the method implemented into study in order to generate the random allocation and the method used to blind the study participants and personnel. We used an open question

The author answered: our pharmacist provided us with coded blank pills, produced by the hospital pharmacy containing either placebo, or misoprostol. Pills were identical and placed in identical numbered containers (1,2,3,4 etc). After the inclusion period ended, the pharmacist gave us the key to the codes used for the medication. This ensured blinding of personnel and participants and proper allocation

Prostaglandins for management of retained placenta (Review) 27

Allocation concealment (selection bias) Low risk After inclusion, a blank envelope was drawn containing study medication and a case record form. The Leiden University Medical Center pharmacist prepared the envelope and study medication. The study medication was provided in a single num- ber coded container Comment: proba- bly done

Blinding of participants and personnel Low risk The blinding was broken after randomi-(performance bias) sation to some women, according to theAll outcomes obstetrician judgment by Breastfeed- ing reasons... during postpartum stage. Is unlikely to suffer performance bias because the physicians were not aware of the treat- ment given and a time limit of 45 minutes was established for manual removal the pla- centa

Blinding of outcome assessment (detection High risk Blood transfusion: the author did notbias) mention any used criteria. The blindingAll outcomes was broken after randomisation to some women, according to the obstetrician judgment during postpartum stage. Some clinicians could have knowledge about the womens intervention. Comment: No blinding or incomplete blinding, and the outcome measurement is likely to be influ- enced by lack of blinding

Incomplete outcome data (attrition bias) High risk Follow-up data were available for 38All outcomes (78%) women in the misoprostol group and 44 (86%) women in the placebo group Follow-up data for side-effects were incom- plete with a level of missing data more than 20%

Selective reporting (reporting bias) High risk Blood transfusion and postpartum haem- orrhage were not pre specified in the pro- tocol stage (ISRCTN45330307) but were reported during the publication

Other bias Low risk Study appear to be free of other sources of

bias.

HELLP: haemolysis elevated liver enzymes and low platelets syndrome

Prostaglandins for management of retained placenta (Review) 28

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.IU: international unit

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Habek 2007 Not a randomised controlled trial.

Harara 2011 Different intervention.

Notten 2012 Not a randomised controlled trial.

Paavonen 2012 Not a randomised controlled trial.

Rogers 2007 Randomised controlled trial, different intervention.

Sundaram 2007 Not a randomised controlled trial.

Prostaglandins for management of retained placenta (Review) 29

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.DATA AND ANALYSES

Appendix 6. metaRegister of Controlled Trials (mRCT) search strategy

CONTRIBUTIONS OF AUTHORSCarlos Fernando Grillo-Ardila and Ariel Ivn Ruiz-Parra conducted the titles selection, assessed trial quality, extracted data, carried outdata analysis and wrote the first draft of the systematic review and subsequent amendments. Hernando G Gaitn assessed trial quality,carried out data analysis and commented on and revised the first draft of the systematic review. Nelcy Rodriguez-Malagn commentedon and revised the first draft of the systematic review.

Prostaglandins for management of retained placenta (Review) 42

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.DECLARATIONS OF INTERESTNone known.

SOURCES OF SUPPORT

Internal sources No sources of support supplied

External sources Universidad Nacional de Colombia, Colombia.

Prostaglandins for management of retained placenta (Review) 43

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.